The immune system is an extraordinarily complex combination of cells and compositions to protect a mammalian host against a wide variety of pathogens, while surveiling the body against aberrations, such as neoplasia. One branch of the immune system involves T cells, which derive their designation by the fact that they are processed by the thymus. The T cells are a complex group of cells which differ as to markers such as CD3, CD4 and CD8, as well as other markers which indicate whether the T cells are in the quiescent or activated state, the homing receptors, which determine the tissue to which T cells will be directed and extravasate, as well as the nature of the targets for the T cells. The T cells may be cytotoxic, having numerous mechanisms for inducing cell death, or activating, by secreting various cytokines which activate other cells.
Among the various subsets of T cells are T cells referred to as cytotoxic T lymphocytes (“CTL”). The CTLs act by being restricted to a particular major histocompatibility complex antigen complex. The CTLs carry a receptor called the T cell receptor, which comprises an a chain and a β chain, with the two chains being polymorphic. The α and β chains of the T cell receptor have specific affinity for a particular MHC complex associated with a peptide in the groove of the MHC. The CTLs have been screened so that the CTLs do not act against cells where the peptide in the groove is endogenous to the host. Where the MHC is foreign or the peptide in the groove is foreign to the host, the CTLs will attack such cell and kill it. There are a variety of pathways by which CTLs may kill target cells.
Other lymphocytic cells involved in the immune system include Natural Killer (NK) cells, which do not carry the markers normally associated with B and T lymphocytes. As distinct from CTL cells, the NK cells have a more random repetoire than the CTL cells. The NK cells appear to lyse certain tumor cells and cells lacking expression of certain MHC proteins, but do not normally lyse normal cells. The NK cells, in common with CTL cells, express a surface ganglioside called asialo GM-1, CD2, and CD16.
While the monitoring function is extremely important to a host's health, there are a number of situations where activation of CTLs is undesired. One particular area is associated with transplantation, where one rarely has an identical match between the donor and recipient of the MHC antigens. Another incidence is where there is a failure on the part of the CTLs in that they attack cells where the peptide and MHC are both endogenous, as occurs in autoimmune diseases.
Immunosuppression has become a general approach in situations where activation of CTLs is undesired. However, immunosuppressants such as cyclosporin A, FK506, and the like, have numerous side effects which are undesirable. There is, therefore, substantial interest in identifying new agents which can act to inhibit the activation of CTLs while having less of a universal effect on the immune system and fewer side effects, so as to leave the host with a substantial proportion of the immune system for protection against adventitious infection.
Relevant Literature
Buelow et al., Transplantation (1995) 59:649–654 and references cited therein.